ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.453+1G>T (rs267607750)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075712 SCV000106716 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
GeneDx RCV000160522 SCV000211088 likely pathogenic not provided 2018-09-18 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.453+1G>T or IVS5+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 5 of the MLH1 gene. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in at least one individual who was reported to have colon, jejunum and renal cancer all under the age of 50 (Zhang 2015). We consider this variant to be likely pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075712 SCV000592359 pathogenic Lynch syndrome 2014-10-10 criteria provided, single submitter clinical testing
Counsyl RCV000576794 SCV000677752 pathogenic Lynch syndrome II 2016-12-13 criteria provided, single submitter clinical testing
Invitae RCV000704046 SCV000832979 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-09 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Lynch syndrome-related cancer (PMID: 23747338, 25892863, 18931482, 26681312). ClinVar contains an entry for this variant (Variation ID: 90223). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV001022649 SCV001184409 likely pathogenic Hereditary cancer-predisposing syndrome 2020-02-25 criteria provided, single submitter clinical testing The c.453+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 5 of the MLH1 gene. This alteration has been reported in one Chinese family meeting Lynch syndrome criteria and is predicted to induce a large splicing event (Sheng JQ et al. Cytogenet. Genome Res., 2008 Oct;122:22-7; Xiong HY et al. Science, 2015 Jan;347:1254806). This alteration was also seen in a Chinese individual with jejunum, colon, renal, and pancreatic cancer all before age 50. Family history included a mother that passed from rectal cancer at age 45 (Zhang JX et al. World J. Gastroenterol., 2015 Apr;21:4136-49). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

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